PROJECT SUMMARY/ABSTRACT The Lung Cancer Program (LCP) includes 70 members (34 primary, 35 associate, 1 adjunct) from 19 departments. The program is led by Dr. John Heymach, an expert in biomarker-driven clinical trials and therapeutic targeting who oversees the program; Dr. Jack Roth, a surgeon-scientist and co-PI of the University of Texas Lung SPORE; and Dr. Lauren Byers, who leads the program's clinical research efforts and mentoring of trainees, fellows, and junior faculty. The major scientific goal of the LCP is to develop more effective and personalized approaches for the treatment of lung cancer. To achieve this goal, the program has 3 specific aims that focus on 3 themes: 1) lung cancer signaling and therapeutic targets; 2) targeting the immune system and microenvironment; and 3) the multimodal treatment of localized and advanced lung cancer. The annual direct peer-reviewed funding totals $5.7M, including an NCI Lung Cancer SPORE, a Stand Up 2 Cancer Dream Team Award, and 3 CPRIT Multi-Investigator Research Awards. Of the total funding, $3.4M (60%) is from NCI grants. Since the last competitive renewal, total annual peer-reviewed direct-cost funding has increased by 93%. Since the last submission, the program has published 999 papers: 550 (55%) intra-programmatic collaborations, 355 (36%) inter-programmatic collaborations, and 607 (61%) external collaborations. Forty-four percent of the publications appeared in journals with an IF >5, and 15% appeared in journals with an IF >10, including Science, N Engl J Med, Proc Natl Acad Sci USA, Cancer Discov, and Lancet Oncol. During the last grant period, program members had leadership roles in standard-of-care?changing studies, including the AURA3 study (establishing osimertinib for EGFR T790M?mutant NSCLC) and a study demonstrating the benefit of local consolidative therapy for patients with oligometastatic NSCLC. Our previous findings identifying novel targets in small cell lung cancer (SCLC) have been validated in subsequent clinical studies. Members also identified 3 subsets of KRAS- mutant NSCLC based on co-occurring genomic alterations that exhibit distinct biology, patterns of immune- system engagement, and therapeutic vulnerabilities. Finally, they identified a role for epithelial-to-mesenchymal transition in regulating tumor immunosuppression via an miR200/ZEB1/PD-L1 axis, playing a central role in promoting NSCLC metastasis. In upcoming years, members will build on these findings to identify new approaches to target subsets of lung cancer, with a focus on SCLC and KRAS-mutant NSCLC; investigate strategies for enhancing antitumor immunity and mechanisms of immunotherapy resistance; and develop multidisciplinary paradigms integrating immunotherapy and targeted agents as an approach to improve the survival of lung cancer patients.